Despite recent and significant advances in neurotherapeutics, which have led to more than 7000 small-molecule drugs, very few (5%) are available to treat Central Nervous System (CNS) diseases and these only treat four main disorders: depression, schizophrenia, epilepsy, and chronic pain. The unavailability of so many promising drugs is due to the impermeability of the blood-brain barrier (BBB). Because of this, devastating CNS disorders and age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis (MS) and amythrophic lateral sclerosis (ALS) remain essentially clinically untreated despite the availability of potentially effective pharmacological agents. Developing methods to traverse the BBB has proven to be a difficult challenge. Despite a myriad of techniques that have recently been developed to successfully achieve trans-BBB transport of neurotherapeutics, there are very few effective treatments for most central nervous system (CNS) disorders and, of those, none can noninvasively induce localized BBB opening. The only noninvasive and localized technique for opening the BBB is focused ultrasound (FUS). The underlying hypothesis of this study is that FUS can open the BBB safely, reversibly, noninvasively, and with regional selectivity, thereby providing a means for the development of novel methods of safe and localized treatment of neurodegenerative diseases. The primary objectives of this study are 1) to optimize such an FUS procedure in vivo, 2) to establish its efficacy and safety profiles, and 3) to demonstrate its feasibility in the presence of neurodegenerative disease. Achieving the goals of the proposed study holds great promise for selectively and precisely delivering pharmacological agents to brain regions most affected by neurodegenerative disease while leaving normal regions intact. The specific aims of the study are therefore to: 1) optimize the FUS technique for BBB opening in a subcortical region typically affected by neurodegenerative disease and establish reproducibility and timeline of opening in wild-type mice; 2) determine the mechanism and safety of the BBB opening with histology; and 3) demonstrate feasibility of trans-BBB molecular delivery for the treatment of neurodegenerative diseases in a transgenic mouse model of Alzheimer's disease. If this technique is shown to be safe and reproducible in vivo, available compounds, previously shelved due to poor BBB permeability, might finally reach the specific brain regions affected by CNS diseases they were designed to treat through FUS-induced localized and safe targeting. Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain undertreated despite the thousands of pharmacological agents available. The objective of this study is to determine how the blood-brain barrier can be opened safely, noninvasively and with regional selectivity using focused ultrasound (FUS) so that drug delivery is successfully achieved in the regions of the brain inflicted by these undertreated and potentially devastating diseases. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]